Primary objective:• To evaluate biodistribution of 89Zr-atezolizumab in patients with high risk DLBCL at diagnosis.Secondary objective:• To assess the heterogeneity of 89Zr-atezolizumab tumor uptake in high-risk DLBCL before R-CHOP.• To correlate…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Description of 89Zr-atezolizumab biodistribution in DLBCL by measuring
standardized uptake value (SUV) on the 89Zr-atezolizumab-PET scans
Secondary outcome
• Tumor and immune cell PD-L1 expression analysis in an archival pre-treatment
biopsy, will be correlated to 89Zr-atezolizumab tumor uptake, evaluated by
measuring standardized uptake value (SUV) on 89Zr-atezolizumab-PET-scans
• Correlation analysis of tumor 89Zr-atezolizumab uptake, evaluated by
measuring standardized uptake value (SUV) and sPD-L1 levels in patient serum,
assessed using ELISA
• Correlation analysis of tumor 89Zr-atezolizumab uptake, evaluated by
assessing immune signature by GEP
• Correlation analysis of 89Zr-atezolizumab uptake and MRD status
• Correlation analysis between 89Zr-atezolizumab off-target uptake and
atezolizumab toxicity
• Analysis of predictive value of 89Zr-atezolizumab imaging in DLBCL patients
Exploratory study endpoints:
• Establish baseline characteristics and dynamics for T-cell repertoire and
microbiome after R-CHOP
Background summary
Patients with a high-risk diffuse large B-cell lymphoma (DLBLC) with an
international prognostic score (IPI) > 2, have a high risk of relapse even
after achieving a metabolic complete remission with R-CHOP chemo-immunotherapy.
Outcome after relapse is dismal. In patients with varies types of relapsed
lymphoma checkpoint inhibition have shown promising results.
In order to improve outcome patients with a high risk DLBCL will be treated in
the HOVON 151 trial (EudracT 2017-002605-35) with the monoclonal antibody
directed against the immune checkpoint program death ligand 1 (PDL1)
atezolizumab for 1 year after achieving a complete metabolic remission with
R-CHOP.
The observed percentage of PD-L1 positive tumor cells in DLBCL cases ranges
from 13 to 31%. For PD-1/PD-L1 checkpoint inhibition PD-L1 tumor surface
expression was proposed as a potential predictive marker. Despite higher
overall response rates in PD-L1 positive malignancies compared to PD-L1
negative tumors, responses are seen in PD-L1 negative patients nevertheless.
PD-L1 status from resected specimens showed a poor correlation to the PDL1
status from matched biopsies. Furthermore it has been shown that PDL1
expression in tumor biopsies changes with treatment. Therefore, PDL1 expression
assessed by one single biopsy might not be representative.
Molecular imaging can be used for the noninvasive assessment of biodistribution
of monoclonal antibodies. Atezolizumab has previously successfully been labeled
with the radionucleotide Zirconium-89 (89Zr) and studied in solid malignancies
(EudracT 2015-000996-29). The results of atezolizumab biodistribution can help
to get a better understanding of the response mechanisms, the relation with
minimal residual disease, the relation with the status of the T-cell and
NK-cell repertoire and toxicity of programmed death ligand 1 (PD-L1) checkpoint
inhibition. Possibly in the future this will facilitate optimal patient
selections. Sequential 89Zr-atezolizumab PET scans can provide information on
the dynamics of atezolizumab biodistribution over time. In combination with
repeated characterization of tumor tissue and blood samples, these results can
give inside in the primary and acquired resistance.
In this parallel study of the HOVON 151 trial 89Zr-atezolizumab-PET-scans will
be used to evaluate 20 DLBCL patients before induction (R-CHOP) therapy, at the
start of atezolizumab consolidation and at suspected relapse.
Study objective
Primary objective:
• To evaluate biodistribution of 89Zr-atezolizumab in patients with high risk
DLBCL at diagnosis.
Secondary objective:
• To assess the heterogeneity of 89Zr-atezolizumab tumor uptake in high-risk
DLBCL before R-CHOP.
• To correlate 89Zr-atezolizumab biodistribution with PD-L1 expression on
tumor cells and cells in the micro-environment as assessed by
immunohistochemistry (IHC) on archival tumor biopsies, soluble PD-L1 (sPD-L1)
measurements and PD-L1 RNA expression (GEP).
• To evaluate 89Zr-atezolizumab biodistribution in metabolic complete
remission following R-CHOP and assess the relation with minimal residual
disease.
• To assess the 89Zr-atezolizumab biodistribution at relapse after treatment
with atezolizumab for patients treated in the HOVON 151 trial.
• Correlate 89Zr-atezolizumab tumor uptake dynamics and biodistribution to
potential adverse reactions of atezolizumab treatment for patients treated in
the HOVON 151 trial
Exploratory objectives:
• To establish the baseline characteristics for the T-cell and NK-cell
repertoire and dynamics induced by R-CHOP.
• To establish the baseline characteristics for the microbiome and the
dynamics induced by R-CHOP.
Study design
Phase II, multicenter, prospective, non-randomized trial:
Part A: 21 eligible patients will undergo a baseline
89Zr-atezolizumab-PET-scans before R-CHOP therapy.
Part B: An estimate of 15 patients who achieved CR after R-CHOP therapy will
undergo a second 89Zr-atezolizumab-PET-scan.
After participation within the imaging trial all eligible patients will be
allowed to enter the HOVON 151 treatment trial.
Part C: Patients with suspected relapse in the HOVON 151 trial will undergo one
additional 89Zr-atezolizumab-PET-scan.
Study burden and risks
For this 89Zr-atezolizumab imaging side study patients have to make max. 4
extra visits to the clinic for screening, to receive tracer injection
and 1 PET scan in each Part of the study (A,B and C). Because of the minimal
modifications accompanying the labeling process of atezolizumab, the toxicity
profile of 89Zr-atezolizumab is expected to be similar to that of atezolizumab.
Based on the experience of the trial in solid malignancy, 89Zr-atezolizumab is
unlikely to pose a toxicological threat, because the tracer is administered at
a non-therapeutic dose of 11 mg. 89Zr-atezolizumab-PET-scans implement a
radiation burden of 19.5 mSv. Besides PET imaging, patients will be asked to
give in total 2 additional blood samples (20 mL) and a fecal sample which will
give minor discomfort. The risk associated with the 89Zr-atezolizumab-PET-scans
seems minor and although patients do not directly benefit from this
89Zr-atezolizumab imaging study, results of this study will be valuable for our
understanding of the tumor immune response and will guide further prospective
research. After participation within the 89Zr-atezolizumab imaging study all
patients will be allowed to enter the HOVON 151 treatment trial, provided they
continue to meet the eligibility criteria to participate in the HOVON 151 trial
and to receive atezolizumab. The HOVON 151 trial aims at improving DFS in
high-risk DLBCL patients with atezolizumab consolidation.
HOVON Centraal Bureau, VUMC, De Boelelaan 1117
Amsterdam 1081 HV
NL
HOVON Centraal Bureau, VUMC, De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria, • Age 18-75 (inclusive) years
• Patients with a confirmed histologic diagnosis of diffuse large B-cell
lymphoma (DLBCL-NOS)
based upon a representative histology specimen according to the WHO
classification, revision 2016
(see appendix A)
• Ann Arbor stages II-IV
• Negative pregnancy test at study entry
• Patient is willing and able use adequate contraception during and until 5
months after the last
protocol treatment.
• Written informed consent
• Patient is capable of giving a written informed consent
Exclusion criteria
Diagnosis
• All histopathological diagnoses other than DLBCL-NOS according to the WHO
classification, revision 2016, including:
- High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6
translocations
- Testicular large B-cell lymphoma
- Primary mediastinal B cell lymphoma
- Transformed indolent lymphoma
- Post-transplant lymphoproliferative disorder, Organ dysfunction
• Clinical signs of severe pulmonary dysfunction
• Clinical signs of heart failure (NYHA classification II-IV)
• Symptomatic coronary artery disease or cardiac arrhythmias not well
controlled with medication.
• Myocardial infarction during the last 6 months
• Significant renal dysfunction (serum creatinine >= 150 umol/l or clearance <=
30ml/min
Creatinine clearance may be calculated by Cockcroft -Gault formula:
CrCl = (140 - age [in years]) x weight [kg] (x 0.85 for females) /
(0.815 x serum creatinine [µmol/L])
• Inadequate hematological function: hemoglobin < 5.5 mmol/L ANC <
1.0x10^9/L or platelets < 75x10^9 /L
• Spontaneous INR > 1.5, aPTT >33
• Significant hepatic dysfunction (total bilirubin >= 1.5x upper limit of normal
(ULN) or transaminases >= 2.5 x ULN), unless related to Gilberts syndrome.
• Clinical signs of severe cerebral dysfunction
• Patients with a history of uncontrolled seizures, central nervous system
disorders or psychiatric disability judged by the investigator to be clinically
significant and adversely affecting compliance to study drugs
• Major surgery within the last 4 weeks, Known or suspected infection
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other
infection or any major episode of infection requiring treatment with IV
antibiotics or hospitalization within 4 weeks before date of registration.
Suspected active or latent tuberculosis needs to be confirmed by positive
interferon gamma (IFN-γ) release assay
• Patients known to be HIV-positive
• Active chronic hepatitis B or C infection
• Administration of a live, attenuated vaccine within 4 weeks before date of
registration or anticipation that such a live attenuated vaccine will be
required during the study and for a period of 5 months after discontinuation of
atezolizumab., Auto-immune
• Any active or history of documented autoimmune disease, including but not
limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular
thrombosis associated with antiphospholipid syndrome, Wegener*s granulomatosis,
Sjögren*s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or
glomerulonephritis.
The following exceptions are allowed: Patients with autoimmune-related
hypothyroidism or type 1 diabetes mellitus who are on stable treatment.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or
evidence of active pneumonitis per chest CT scan at screening.
• Patients with uncontrolled asthma or allergy, requiring systemic steroid
treatment
• Regular treatment with corticosteroids within the 4 weeks prior to date of
registration, unless administered for indications other than NHL at a dose
equivalent to < 30 mg/day prednisone/prednisolone., General
• Serious underlying medical conditions, which could impair the ability of the
patient to participate in the trial (e.g. ongoing infection, uncontrolled
diabetes mellitus, gastric ulcers, active autoimmune disease)
• Current participation in another clinical trial interfering with this trial
• History of active cancer during the past 5 years, except basal cell carcinoma
of the skin or stage 0 cervical carcinoma
• Life expectancy < 6 months
• Any psychological, familial, sociological and geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule, Prior treatment
• Prior treatment with atezolizumab, or anti PD-1 or PDL-1 antibodies.
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-CTLA4 therapeutic antibodies.
• Treatment with systemic immunostimulatory agents (including but not limited
to IFN, interleukin [IL]-2) within 6 weeks or 5 half-lives of the drug,
whichever is shorter, prior to date of registration.
• Treatment with systemic immunosuppressive medications, including but not
limited to prednisone, cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-tumor necrosis factor (anti-TNF) agents within 2 weeks
prior to date of registration; inhaled corticosteroids and mineralocorticoids
are allowed.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003511-20-NL |
| CCMO | NL63047.042.18 |